Non-steroidal anti-inflammatory drugs, commonly abbreviated NSAIDs, are well-known drugs for the treatment of pain and inflammation. One of the major drawbacks with NSAIDs is that they have severe gastro-intestinal side effects. Patients undergoing treatment with NSAIDs for a longer period of time, such as naproxen, often experience problems with stomach gastrointestinal side effects.
Nitrogen oxide releasing NSAID compounds (in the following NO-releasing NSAIDs), have recently been found to have an improved side-effect profile, see e.g. WO 94/04484, WO 94/12463, WO 95/09831 and WO 95/30641.
NO-releasing NSAIDs are lipophilic compounds with poor aqueous solubility. They can be classified into class 2 according to the Biopharmaceutical Classification System proposed by Amidon et al. (Pharm. Res. 12 (1995) pp. 413-420). Drugs of this class are characterised by low aqueous solubility but reasonably well permeability. A biopharmaceutical problem with these compounds is that their absorption from the gastrointestinal tract (GIT) may be dissolution rate limited, resulting in poor bioavailibility upon oral administration.
WO 95/08983 discloses a self-emulsifying composition for oral administration that forms a microemulsion in situ when in contact with biological fluids. This composition can be characterised as a self-microemulsifying drug delivery system (SMEDDS), and comprises at least                an active compound,        lipophilic phase consisting of a mixture of glycerides and fatty acid esters,        a surface-active agent,        a co-surfactant, and        a hydrophilic phase, which is achieved after ingestion by the physiological liquid of the digestive medium.        
The present invention distinguishes in several aspects from WO 95/08983 and other SMEDDS.
U.S. Pat. No. 5,929,030 discloses pre-concentrate of a microemulsion as a suitable pharmaceutical composition for a water-insoluble pharmaceutically active substance such as cyclosporin. The composition, that forms a microemulsion, comprises a) a water-insoluble pharmaceutically active material; b) a lipophilic phase comprising a mixture of glycerides, and c) a phospholipid and another surfactant.
Whereas the compositions disclosed in WO 95/08983 and in U.S. Pat. No. 5,929,030 form a microemulsion in situ, the compositions of the present invention form an emulsion. EP 274 870 discloses a pharmaceutical composition comprising a non-steroidal anti-inflammatory drug (NSAID) and a surfactant, the composition being capable of forming micelles containing the NSAID upon oral administration. These micelles have been found to present a particularly appropriate form to administer NSAIDs orally, alleviating their adverse effects on the gastrointestinal tract (GIT). Micelles are aggregates in which the surfactant molecules are generally arranged in a spheroidal structure with the hydrophobic region at the core shielded, in an aqueous solution, from the water by a mantle of outer hydrophilic regions. The drug is usually solubilised in the surfactant. Micelles are to be contrasted in terms of their structure with emulsions, which are formed by compositions of the present invention. Whereas micelles are thermodynamically stable one-phase-systems (according to the Gibbs phase law) in which the aggregates usually have a diameter of approximately two lengths of the surfactant molecule forming it, i.e. in the order of some ten to hundred Angstrom (Å), emulsions are much larger aggregates, in the order of nanometers to micrometers in diameter, consisting of an oily core which is surrounded by one or several layers of surfactants. Emulsions are generally two-phase-systems, and they are thermodynamically unstable (but may be kinetically stable). Another major difference between the compositions of EP 274 870 and the present invention is the nature of the active compound. Whereas NSAIDs are crystalline powders by nature, the NO-releasing NSAIDs or mixtures of NO-releasing NSAIDs used in the present invention are in oil form or in a semisolid form. Moreover, micelles usually require a much higher drug:surfactant ratio compared to the oil:surfactant ratio required to form an emulsion.
One of the unique features with NO-releasing NSAIDs is that many of these compounds are oils or thermosoftening semisolids, which are practically insoluble in water. With high-dose NO-releasing NSAIDs, e.g. when the dose is above about 350 mg, it is difficult to formulate a tablet of reasonable size of the large amount of oil or semisolid. The lipophilic NO-releasing NSAIDs can, however, be formulated as oil-in-water emulsions where the compound constitutes, or is part of, the oil phase emulsified in water by one or more surfactants. An addition of a lipophilic solubiliser phase is not needed for the present invention since the active compound, the NO-releasing NSAID, is able to solely constitute the oil phase of the in situ emulsion. Further, the addition of a co-surfactant can be avoided by the present invention, i.e. the toxicological concern is reduced to a minimum. In pharmacokinetic animal studies it has been surprisingly found that such oil-in-water emulsions of NO-releasing NSAIDs display a much better bioavailability compared to the unemulsified substance. A problem with emulsions is, however, that they are thermodynamically unstable and have poor long-term storage stability since they often tend to coalescence, creaming/sedimentation or phase separation. It is inter alia not possible to fill oil-in-water emulsions into gelatine capsules since the high water content of the emulsion is incompatible with the capsule shell and would dissolve it.